Uncoupling the Coupled Calcium and Zinc Dyshomeostasis in Cardiac Myocytes and Mitochondria Seen in Aldosteronism
| Autor: | Yao Sun, Atta U. Shahbaz, Ivan C. Gerling, Syamal K. Bhattacharya, Wenyuan Zhao, Patti L. Johnson, Robert A. Ahokas, Tieqiang Zhao, German Kamalov, Karl T. Weber |
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| Rok vydání: | 2010 |
| Předmět: |
Male
inorganic chemicals medicine.medical_specialty Pyrrolidines Mitochondrion medicine.disease_cause Antioxidants Mitochondria Heart Article Rats Sprague-Dawley chemistry.chemical_compound Pyrrolidine dithiocarbamate Thiocarbamates Internal medicine Hyperaldosteronism medicine Animals Homeostasis Myocyte Myocytes Cardiac Channel blocker Pharmacology Aldosterone Hydrogen Peroxide Oxidants Zinc Sulfate Rats Oxidative Stress Zinc Endocrinology chemistry Calcium Amlodipine Cardiology and Cardiovascular Medicine Intracellular Oxidative stress |
| Zdroj: | Journal of Cardiovascular Pharmacology. 55:248-254 |
| ISSN: | 0160-2446 |
| Popis: | Intracellular [Ca2+]i overloading in cardiomyocytes is a fundamental pathogenic event associated with chronic aldosterone/salt treatment (ALDOST) and accounts for an induction of oxidative stress that leads to necrotic cell death and consequent myocardial scarring. This prooxidant response to Ca2+ overloading in cardiac myocytes and mitochondria is intrinsically coupled to simultaneous increased Zn2+ entry serving as an antioxidant. Herein, we investigated whether Ca2+ and Zn2+ dyshomeostasis and prooxidant to antioxidant dysequilibrium seen at 4 weeks, the pathologic stage of ALDOST, could be uncoupled in favor of antioxidants, using cotreatment with a ZnSO4 supplement; pyrrolidine dithiocarbamate (PDTC), a Zn2+ ionophore; or ZnSO4 in combination with amlodipine (Amlod), a Ca2+ channel blocker. We monitored and compared responses in cardiomyocyte free [Ca2+]i and [Zn2+]i together with biomarkers of oxidative stress in cardiac myocytes and mitochondria. At week 4 of ALDOST and compared with controls, we found (1) an elevation in [Ca2+]i coupled with [Zn2+]i and (2) increased mitochondrial H2O2 production and increased mitochondrial and cardiac 8-isoprostane levels. Cotreatment with the ZnSO4 supplement alone, PDTC, or ZnSO4+Amlod augmented the rise in cardiomyocyte [Zn2+]i beyond that seen with ALDOST alone, whereas attenuating the rise in [Ca2+]i, which together served to reduce oxidative stress. Thus, a coupled dyshomeostasis of intracellular Ca2+ and Zn2+ was demonstrated in cardiac myocytes and mitochondria during 4-week ALDOST, where prooxidants overwhelm antioxidant defenses. This intrinsically coupled Ca2+ and Zn2+ dyshomeostasis could be uncoupled in favor of antioxidant defenses by selectively increasing free [Zn2+]i and/or reducing [Ca2+]i using cotreatment with ZnSO4 or PDTC alone or ZnSO4+Amlod in combination. |
| Databáze: | OpenAIRE |
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